Regulated actin assembly is a critical component of immune cell function, as genetic and pharmacological inhibition of actin cytoskeletal dynamics renders immune cells incapable of performing many of their effector functions: Actin assembly regulation is a complex process that involves many proteins including actin nucleators as well as their activators and effectors. The exact role and distinct modes of actin nucleation have yet to be elucidated in immune cells and how these processes affect immune cell functions. Activators of actin nucleation including cortactin have been largely studied in cells of non-hematopoietic lineage. However, in cells of hematopoietic lineage, adhesion, migration and actin cytoskeletal dynamics are highly regulated as to prevent unwarranted immune cell functions. Arp2/3 and formins are two distinct actin nucleators and HS1 is a known activator of Arp2/3, yet their roles in immune cell functions and in particular NK cells remains incompletely understood. Clinically, NK cells are capable of promoting bone marrow rejection and as well as engraftment, in addition, Nk cells elicit potent anti-tumor effects. The clinical relevance of NK cells has begun to be appreciated and new clinical studies utilizing NK cells for the treatment of cancer patients have begun to be met with modest success. However with only limited understanding as to how NK cells interact with target cancer cells, it will be difficult to advance NK immunotherapy. Following completion of the experiments in this proposal, there will be greater understanding of the role that regulated actin assembly plays in the ability of NK cells to carry out their functions critical to immune tumor surveillance necessary for the survival of higher eukaryotes.